DREADD Ligands

DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) are genetically modified G-protein coupled receptors (GPCRs) that are activated by physiologically inert designer synthetic ligands (designer drugs), known as DREADD ligands. They can be used to modulate neuronal activity, and also to investigate GPCR signaling pathways.

Literature (4)


Cat. No. Product Name / Activity
4936 Clozapine N-oxide
Activator of muscarinic DREADDs
6329 Clozapine N-oxide dihydrochloride
Activator of muscarinic DREADDs; water soluble version of Clozapine N-oxide (Cat. No. 4936)
5548 DREADD agonist 21
Potent muscarinic DREADD agonist
6422 DREADD agonist 21 dihydrochloride
Potent muscarinic DREADD agonist; water soluble version of DREADD agonist 21 (Cat. No. 5548)
4349 Olanzapine
Highly potent hM4Di activator; also 5-HT2A and D2 antagonist
5549 Perlapine
Potent muscarinc DREADD agonist
5611 Salvinorin B
Activates the κ-opioid DREADD (KORD)
7119 Sorbic acid
Activator of hFFA2-DREADDs

Studies have provided evidence that DREADDs are functionally similar to their wild type receptors, therefore they are useful tools for the study of GPCR signaling.

The first DREADDs to be developed were derived from human muscarinic acetylcholine receptors (mAChRs) and termed hM1-5D. These receptors have mutations in their orthosteric binding site, abolishing their affinity for the endogenous ligand ACh, while rendering them responsive to the small molecule clozapine-N-oxide (CNO). CNO exhibits no appreciable affinity (Ki >1 μM) for any other relevant CNS target, and therefore is a selective tool for the activation of DREADDs.

DREADD Ligands Mechanism of Action

Signaling pathways for DREADD Ligands DREADD agonist 21, CNO and Salvinorin B.

Figure 1: Binding of DREADD ligands to Gαq-DREADDs provokes neuronal firing, whereas binding to Gαi-DREADDs results in inhibition of neuronal activity. Clozapine N-oxide dihydrochloride and DREADD agonist 21 are non-selective muscarinic DREADD agonists and so can activate or inhibit neuronal activity, depending on the specific receptor being expressed. Salvinorin B is selective for the KORD receptor, which is coupled to Gαi signaling; consequently binding results in inhibition of neuronal activity.

DREADDs have been shown to be effective for the modulation of neuronal activity. hM3Dq is a Gq-coupled GPCR that activates neuronal firing upon CNO stimulation, while hM4Di is a Gi-coupled GPCR that inhibits neuronal firing through activation of GIRK (Kir3) channels. These DREADDs have also been shown to have applications in vivo. Activation of hM3Dq expressing locus coeruleus neurons by CNO enhanced memory in a mouse model of Down syndrome. Furthermore injection of hM3Dq into the paraventricular hypothalamus (PVH) suppressed hyperphagia in PVH LMO4-deficient obese mice, with activation of hM4Di having the opposite effect.

A new DREADD has since been developed from the κ opioid receptor (KOR), and termed KORD. KORD is activated by the pharmacologically inert small molecule salvinorin B, and will enable the simultaneous interrogation of KOR and mAChR signaling. The development of further DREADDs and small molecule DREADD modulators is currently ongoing.

Literature for DREADD Ligands

Tocris offers the following scientific literature for DREADD Ligands to showcase our products. We invite you to request* or download your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.


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